WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISK FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME
Life-Threatening Respiratory Depression
Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with ABSTRAL, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of ABSTRAL or following a dose increase. The substitution of ABSTRAL for anyother fentanyl product may result in fatal overdose.
Due to the risk of respiratory depression, ABSTRAL is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients.
Accidental ingestion of even one dose of ABSTRAL, especially by children, can result in a fatal overdose of fentanyl.
Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. ABSTRAL must be kept out of reach of children.
Cytochrome P450 3A4 Interaction
The concomitant use of ABSTRAL with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving ABSTRAL and any CYP3A4 inhibitor or inducer.
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
• Reserve concomitant prescribing of ABSTRAL and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required
• Follow patients for signs and symptoms of respiratory depression and sedation
Risk of Medication Errors
Substantial differences exist in the pharmacokinetic profile of ABSTRAL compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl and that could result in fatal overdose.
• When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to ABSTRAL.
• When dispensing, do not substitute an ABSTRAL prescription for other fentanyl products.
Addiction, Abuse, and Misuse
ABSTRAL exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing ABSTRAL, and monitor all patients regularly for the development of these behaviors and conditions.
Risk Evaluation and Mitigation Strategy (REMS) Access Program
Because of the risk for misuse, abuse, addiction, and overdose, ABSTRAL is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of ABSTRAL during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
1 INDICATIONS AND USAGE
ABSTRAL is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.
Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine per day, or at least 25 mcg per hour of transdermal fentanyl, or at least 30 mg of oral oxycodone per day, or at least 8 mg of oral hydromorphone per day, or at least 25 mg oral oxymorphone per day, or at least 60 mg oral hydrocodone per day or an equianalgesic dose of another opioid medication daily for a week or longer. Patients must remain on around-the-clock opioids when taking ABSTRAL.
Limitations of Use:
• Not for use in opioid non-tolerant patients.
• Not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or in the emergency department.
• As a part of the TIRF REMS Access program, ABSTRAL may be dispensed only to outpatients enrolled in the program. For inpatient administration of ABSTRAL (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.
2 DOSAGE AND ADMINISTRATION
2.1 Important Dosage and Administration Information
• Healthcare professionals who prescribe ABSTRAL on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of ABSTRAL.
• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
• It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.
• Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.
• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with ABSTRAL and adjust the dosage accordingly.
• Instruct patients and caregivers to take steps to store ABSTRAL securely and to properly dispose of unused ABSTRAL as soon as no longer needed.
• ABSTRAL is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.)..
• ABSTRAL is NOT a generic version of any other oral transmucosal fentanyl product.
2.2 Initial Dosage
Initiate treatment with ABSRTAL for all patients with a single initial dose of 100 mcg. The initial dose of ABSTRAL is always 100 mcg, with the only exception being patients already using Actiq.
• If adequate analgesia is obtained within 30 minutes of administration of the 100 mcg tablet, continue to treat subsequent episodes of breakthrough pain with this dose.
• If adequate analgesia is not obtained after ABSTRAL, the patient may use a second ABSTRAL dose (after 30 minutes) as directed by their healthcare provider. No more than two doses of ABSTRAL may be used to treat an episode of breakthrough pain.
• Patients must wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL.
Due to differences in the pharmacokinetic properties and individual variability, even patients switching from other fentanyl containing products to ABSTRAL must start with the 100 mcg dose except patients switching from ACTIQ.
ABSTRAL is not equivalent on a mcg per mcg basis with all other fentanyl products, therefore, do not switch patients on a mcg per mcg basis from any other fentanyl product. ABSTRAL is NOT a generic version of any other fentanylproduct.
2.3 Titration and Maintenance of Therapy
The objective of dose titration is to identify an effective and tolerable maintenance dose. From an initial dose, closely follow patients and change the dosage strength until the patient reaches a dose that provides adequate analgesia using a single ABSTRAL dosage unit per breakthrough cancer pain episode. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should be removed from the patient’s mouth immediately, disposed of properly, and subsequent doses should be decreased. Patients should record their use of ABSTRAL over several episodes of breakthrough cancer pain and review their experience with their healthcare providers to determine if a dosage adjustment is warranted for management of breakthrough cancer pain episodes. The effective and tolerable dose of Abstral will be determined by dose titration in individual patients.
If adequate analgesia was not obtained with the first 100 mcg dose, continue dose escalation in a stepwise manner over consecutive breakthrough episodes until adequate analgesia with tolerable sideeffects is achieved. Increase the dose by 100 mcg multiples up to 400 mcg as needed. If adequate analgesia is not obtained with a 400 mcg dose, the next titration step is 600 mcg. If adequate analgesia is not obtained with a 600 mcg dose, the next titration step is 800 mcg. During titration, patients can be instructed to use multiples of 100 mcg tablets and/or 200 mcg tablets for any single dose. Instruct patients not to use more than 4 tablets at one time. If adequate analgesia is not obtained 30 minutes after the use of ABSTRAL, the patient may repeat the same dose of ABSTRAL. No more than two doses of ABSTRAL may be used to treat an episode of breakthrough pain. Rescue medication as directed by the health care provider can be used if adequateanalgesia is not achieved after use of ABSTRAL.
The efficacy and safety of doses higher than 800 mcg have not been evaluated in clinical studies in patients.
In order to minimize the risk of ABSTRAL-related adverse reactions and to identify the appropriate dose, it is imperative that patients be supervised closely by health professionals during the titration process.
Once titrated to an effective dose, instruct patients to use only one ABSTRAL tablet of the appropriate strength per dose. Maintain patients on thisdose.
If adequate analgesia is not obtained after use of ABSTRAL, the patient may use a second ABSTRAL dose (after 30 minutes) as directed by their healthcare provider. No more than two doses of ABSTRAL maybe used to treat an episode of breakthrough pain.
Patients must wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL.
If the response (analgesia or adverse reactions) to the titrated ABSTRAL dose markedly changes, an adjustment of dose may be necessary to ensure that an appropriate dose is maintained. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the ABSTRAL dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of breakthrough pain and opioid-related adverse reactions.
If more than four episodes of breakthrough pain are experienced per day, re-evaluate the dose of the long- acting opioid used for persistent underlying cancer pain. If the long-acting opioid or dose of long-acting opioid is changed, re-evaluate and re-titrate the ABSTRAL dose as necessary to ensure the patient is on an appropriate dose.
Limit the use of ABSTRAL to treat four or fewer episodes of breakthrough pain perday.
It is imperative that any dose re-titration is monitored carefully by a healthcare professional.
2.4 Administration of ABSTRAL
Instruct patients to place ABSTRAL tablets on the floor of the mouth directly under the tongue immediately after removal from the blister unit and not to chew, suck, or swallow ABSTRAL tablets. Allow ABSTRAL tablets to completely dissolve in the sublingual cavity. Advise patients not to eat or drink anything until the tablet is completely dissolved.
In patients who have a dry mouth, water may be used to moisten the buccal mucosa before taking ABSTRAL.
2.5 Discontinuation of ABSTRAL
For patients no longer requiring opioid therapy, consider discontinuing ABSTRAL along with a gradual downward titration of other opioids to minimize possible withdrawal effects.
In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, ABSTRAL therapy can usually be discontinued immediately.
2.6 Disposal of ABSTRAL
Patients and their household members must be advised to dispose of any tablets remaining from a prescription as soon as they are no longer needed. Instructions are included in Patient Counseling Information (17) and in the Medication Guide.
To dispose of any unused ABSTRAL tablets, remove them from the blister cards and flush down the toilet. Do not dispose of the ABSTRAL blister cards or cartons down the toilet.
If additional assistance is required, call 1-888-227-8725.
3 DOSAGE FORMS AND STRENGTHS
Sublingual tablets: All tablets are white and available in six strengths, distinguishable by the shape of the tablet and by de- bossing on the tablet surface:
100 microgram tablet: round tablet marked with the number “1
200 microgram tablet: oval-shaped tablet marked with the number “2” 300 microgram tablet: triangle-shaped tablet marked with the number “3” 400 microgram tablet: diamond-shaped tablet marked with the number “4” 600 microgram tablet: “D”-shaped tablet marked with the number “6”
800 microgram tablet: capsule-shaped tablet marked with the number “8”.
ABSTRAL is contraindicated in:
• Opioid non-tolerant patients: Life threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.
• Acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency department.
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
• Known or suspected gastrointestinal obstruction, including paralytic ileus.
• Known hypersensitivity to fentanyl (e.g., anaphylaxis).
5 WARNINGS AND PRECAUTIONS
5.1 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ABSTRAL, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of ABSTRAL.
To reduce the risk of respiratory depression, proper dosing and titration of ABSTRAL are essential. Overestimating the ABSTRAL dosage can result in a fatal overdose with the first dose. The substitution of ABSTRAL for any other fentanyl product may result in fatal overdose.
ABSTRAL could be fatal to individuals for whom it is not prescribed and for those who are not opioid- tolerant.
Accidental ingestion of even one dose of ABSTRAL, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.
5.2 Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure
Death has been reported in children who have accidentally ingested transmucosal immediate–release fentanyl products.
Patients and their caregivers must be informed that ABSTRAL contains a medicine in an amount which can be fatal to a child. Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.
Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible.
Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of ABSTRAL are provided in the ABSTRAL Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.
5.3 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
Concomitant use of ABSTRAL with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of ABSTRAL is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ABSTRAL treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using ABSTRAL with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ABSTRAL-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of ABSTRAL until stable drug effects are achieved.
Concomitant use of ABSTRAL with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using ABSTRAL with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur.
5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ABSTRAL with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant,
prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when ABSTRAL is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.
5.5 Risk of Medication Errors
When prescribing, DO NOT convert a patient to ABSTRAL from any other fentanyl products on a mcg per mcg basis from other fentanyl products as ABSTRAL and other fentanyl products are not equivalent on a microgram per microgram basis.
ABSTRAL is not a generic version of other transmucosal immediate-release fentanyl (TIRF) formulations. When dispensing, do not substitute an ABSTRAL prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and ABSTRAL are not equivalent. Substantial differences exist in the pharmacokinetic profile of ABSTRAL compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of ABSTRAL or any other fentanyl product may result in a fatal overdose.
There are no safe conversion directions available for patients on any other fentanyl products except ACTIQ. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of ABSTRAL should always be 100 mcg.
Each patient should be individually titrated to provide adequate analgesia while minimizing side effects.
5.6 Addiction, Abuse, and Misuse
ABSTRAL contains fentanyl, a Schedule II controlled substance. As an opioid, ABSTRAL exposes users to the risks of addiction, abuse, and misuse.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ABSTRAL. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing ABSTRAL, and monitor all patients receiving ABSTRAL for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as ABSTRAL, but use in such patients necessitates intensive counseling about the risks and proper use of ABSTRAL along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ABSTRAL. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
5.7 Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program
Because of the risk for misuse, abuse, addiction, and overdose, ABSTRAL is available only through a restricted program called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g., hospitals, hospices, and long- term care facilities that prescribe for inpatient use) of ABSTRAL, patient and prescriber enrollment is not required.
Required components of the TIRF REMS Access program are:
• Healthcare professionals who prescribe ABSTRAL must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.
• To receive ABSTRAL, outpatients must understand the risks and benefits and sign a Patient- Prescriber Agreement.
• Pharmacies that dispense ABSTRAL must enroll in the program and agree to comply with the REMS requirements.
• Wholesalers and distributors that distribute ABSTRAL must enroll in the program and distribute only to authorized pharmacies.
Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.
5.8 Neonatal Opioid Withdrawal Syndrome
Prolonged use of ABSTRAL during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of ABSTRAL in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease: ABSTRAL treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ABSTRAL.
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
Monitor such patients closely, particularly when initiating and titrating ABSTRAL and when ABSTRAL is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of ABSTRAL with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue ABSTRAL if serotonin syndrome is suspected.
5.11 Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
5.12 Severe Hypotension
ABSTRAL may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of ABSTRAL. In patients with circulatory shock, ABSTRAL may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ABSTRAL in patients with circulatory shock.
5.13 Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ABSTRAL may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ABSTRAL.
Opioids may obscure the clinical course of a patient with a head injury. Avoid the use of ABSTRAL in patients with impaired consciousness or coma.
5.14 Risk of Use in Patients with Gastrointestinal Conditions
ABSTRAL is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The fentanyl in ABSTRAL may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.
5.15 Increased Risk of Seizures in Patients with Seizure Disorders
The fentanyl in ABSTRAL may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ABSTRAL therapy.
5.16 Risks of Driving and Operating Machinery
ABSTRAL may impair the mental or physical abilities needed to perform of potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ABSTRAL and know how they will react to the medication.
5.17 Cardiac Disease
Intravenous administration of fentanyl may produce bradycardia. Therefore, use ABSTRAL with caution in patients with bradyarrhythmias.
6 ADVERSE REACTIONS
The following serious adverse reactions are described, or described in greater detail, in other sections:
• Life-Threatening Respiratory Depression.
• Interactions with Benzodiazepines and Other CNS Depressants.
• Addiction, Abuse, and Misuse.
• Neonatal Opioid Withdrawal Syndrome.
• Serotonin Syndrome.
• Adrenal Insufficiency.
• Severe Hypotension.
• Gastrointestinal Adverse Reactions.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of ABSTRAL has been evaluated in 311 opioid-tolerant cancer patients with breakthrough pain. Two hundred and seventy (270) of these patients were treated in multiple-dose studies. The duration of therapy for patients in multiple-dose studies ranged from 1-405 days with an average duration of 131 days and with 44 patients treated for at least 12 months.
The clinical trials of ABSTRAL were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistentpain.
The adverse reaction data presented in Table 2 reflect the actual percentage of patients experiencing reactions among patients who received ABSTRAL for breakthrough pain along with concomitant opioid use for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of ABSTRAL therapy or cancer-related symptoms.